22-24495397-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_016327.3(UPB1):c.-7C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,612,786 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: UPB1 NM_016327.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.48

Genes affected

UPB1 (HGNC:16297): (beta-ureidopropionase 1) This gene encodes a protein that belongs to the CN hydrolase family. Beta-ureidopropionase catalyzes the last step in the pyrimidine degradation pathway. The pyrimidine bases uracil and thymine are degraded via the consecutive action of dihydropyrimidine dehydrogenase (DHPDH), dihydropyrimidinase (DHP) and beta-ureidopropionase (UP) to beta-alanine and beta-aminoisobutyric acid, respectively. UP deficiencies are associated with N-carbamyl-beta-amino aciduria and may lead to abnormalities in neurological activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-24495397-C-G is Benign according to our data. Variant chr22-24495397-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 340927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPB1	NM_016327.3	c.-7C>G		5_prime_UTR_variant	1/10	ENST00000326010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPB1	ENST00000326010.10	c.-7C>G		5_prime_UTR_variant	1/10	1	NM_016327.3	P1
UPB1	ENST00000382760.2	c.-7C>G		5_prime_UTR_variant	1/4	5
UPB1	ENST00000415388.5	c.-7C>G		5_prime_UTR_variant, NMD_transcript_variant	1/9	5

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00156 AC: 388 AN: 249428 Hom.: 2 AF XY: 0.00157 AC XY: 212 AN XY: 135064

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.000246

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00212 AC: 3092 AN: 1460432 Hom.: 5 Cov.: 33 AF XY: 0.00209 AC XY: 1516 AN XY: 726610

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.000442

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74498

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00139

EpiCase AF: 0.00305

EpiControl AF: 0.00279

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of beta-ureidopropionase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.54
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200677387; hg19: chr22-24891365;